Table 1.

Summary of transgenic models, phenotypes, and effects of SUMOylation (extra-nuclear events).

Molecule	Transgenic model	Model characteristics	Phenotypes and the effect of SUMOylation
KCNA5 (Kv1.5)	Kcna5 Replace mKv1.5 with 4-aminopyridine (4-AP)-insensitive channel rat Kv1.1 (SWAP mice) [162]	Non-lethal	4-AP-sensitive component of I (K, slow) was absent No α-dendrotoxin-sensitive current and no 4-AP-induced prolongation of QTc. No increase in arrhythmia during ambulatory telemetry monitoring [162]. De-SUMOylation of KCNA5 induced hyperpolarizing shift in the voltage dependence of steady-state inactivation [24]
KCNK1	Kcnk1−/− [163]	Non-lethal	Impaired regulation of Pi transport in proximal tubule and water transport in medullary collecting duct [163]. KCNK1 regulates sinus rhythm after bran ischemia [31]. KCNK1 SUMOylation inhibited KCNK1 current [32].
SERCA2a	Cardiac specific-Serca2a−/− [164]	Approximately 20% increase in embryonic and neonatal mortality. Major cardiac malformations were observed in embryonic lethal mice [164].	Adult mice showed a reduced spontaneous nocturnal activity and developed a mild compensatory concentric cardiac hypertrophy with impaired cardiac contractility and relaxation. Ca2+ uptake levels were reduced. Relaxation and Ca2+ removal by the SR were significantly reduced [164]. SERCA2a SUMOylation stabilized SERCA2a and improve cardiac function via upregulating its activity and expression [34].
DRP1	Cardiac specific-inducible Drp1−/−	Inducible knock out.	Mitochondrial enlargement, lethal dilated cardiomyopathy, and cardiomyocyte necrosis. DRP1 SUMO1 modification increase mitochondrial fission and hyper-fragmentation, leading to apoptosis in Cos7 and HeLa cell. DRP1 SUMO2 modification inhibited apoptosis via reducing the association of DRP1 with mitochondria.
NEMO	Nemo−/− Cardiac specific Nemo−/− [69]	Males homozygous for targeted null mutations exhibit embryonic lethality by embryonic day 13.5 from apoptotic liver damage [165].	Heterozygous females show dermatopathy (patchy skin lesions with granulocyte infiltration), which is similar to the human X-linked disorder incontinentia pigmenti [166]. Sever liver degeneration and lack of NF-κB activation [165]. Adult-onset dilated cardiomyopathy. Increasing oxidative stress, inflammation and apoptosis [69]. NENO SUMOylation increases IKK and NF-κB activation [76].
PKCα	PKCα−/− Cardiac specific PKCα−/− [80]	Non-lethal.	Enhance insulin signaling through PI3-K [167]. Increases cardiac contractility and protects against heart failure [80]. PKCα SUMOylation inhibits PKCα kinase activation [78].
AMPK	Ampkα1−/− [168,169] Ampkα2−/− [168,170] Ampkβ1β2−/− Skeletal and heart specific (under the control of muscle creatine kinase promoter) Ampkβ1β2−/− [171] Kinase dead Ampkα2 transgenic mice with muscle creatine kinase promoter (skeletal and cardiac expression) [87].	Non-lethal Non-lethal Homozygous embryonically lethal Non-lethal Non-lethal	Anemia, reticulocytosis, splenomegaly, increased erythrocyte turnover, and elevated plasma erythroprotein levels [169]. Hyperglycemic, hypoinsulemic, and insulin resistance [168,170]. Physically inactive with reductions in skeletal muscle mitochondrial content. Impaired contraction-stimulated glucose uptake [171]. Maintain glucose uptake and glycolysis during ischemia and reperfusion in vitro, and show no increase of fatty acid oxidation during reperfusion in vivo. Impaired recovery of left ventricle contractile function after ischemia/reperfusion via increasing apoptosis and lowering ATP content in vivo [87]. AMPKβ2 SUMOylation (SUMO2) increases AMPK activation and inhibits its ubiquitin-dependent degradation [94].
LKB1	Lkb1−/− [172]	Homozygous embryonically lethal	Neural tube defects, mesenchymal cell death, and vascular abnormalities. Tissue specific deregulation of vascular endothelial growth factor (VEGF) expression [172]. LKB1 SUMOylation (SUMO1) promotes LKB1 association with AMPKα and accelerates AMPK activation [95].
UBC9	Cardiac specific Ubc9 overexpression [97]	Non-lethal	Increased autophagy. Reduced aggregate formation, decreased fibrosis, reduced hypertrophy, and improved cardiac function and survival in a mutant α-B crystallin mice (CryAB(R120G)) [97]. UBC9 is a SUMO E2 conjugating enzyme.